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Copper plays a role in how the brain regulates sleep, suggests a new study in zebrafish.

Christopher J. Chang and coworkers at the University of California, Berkeley, induced a copper deficiency in zebrafish by genetically engineering the animals to express a mutated version of a protein responsible for copper uptake. This modification made the fish sluggish and disrupted their sleep-activity cycle (Nat. Chem. Biol. 2018, DOI: 10.1038/s41589-018-0062-z).

“We show that just modulating the copper status has grave consequences for sleep behavior,” Chang says. The fish were harder to wake and they became more tired during their day compared with normal fish, he notes.

The researchers suspected that copper might be important for sleep because it’s needed by the enzyme dopamine β-hydrolase. The enzyme is involved in the biosynthesis of the neurotransmitter norepinephrine in a part of the brain known as the locus coeruleus. This region is involved in many behaviors, including sleep, and the neurotransmitter is responsible for much of the region’s activity. “You only get the synthesis of norepinephrine if you have sufficient amounts of copper, which is required to activate this enzyme,” Chang says.

The researchers imaged the distribution of copper in zebrafish brains with the help of a new pair of fluorescent probes, one that responds to copper and one that serves as a control. The probes are the same size and shape. The difference between the probes is in the number of sulfur atoms capable of coordinating with the metal. The copper-responsive one has four sulfurs. In the control probe, two sulfurs have been replaced by carbons.

The team also used a complementary probe-free method—laser ablation inductively coupled mass spectrometry—to measure copper levels. Both methods indicated that the locus coeruleus was highly enriched in copper.

Anthony White, a neurodegeneration expert at the University of Melbourne, calls the work “a great example of how traditional chemical and biophysical approaches to understanding copper can be combined with genetic approaches to tease out new roles for copper in biology.”

CORRECTION:

The structure in this story was updated on June 8, 2018, to correct a typo in the control probe label.